Cyclic peptides for treatment for cachexia

a peptide and peptide technology, applied in the field of cyclic peptides, can solve the problems of obesity in mice, undesired loss of body weight, etc., and achieve the effects of low dose, efficacy, and efficacy

Inactive Publication Date: 2008-03-11
PALATIN TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0066]According to one embodiment of the present invention, there is provided a C-terminus hydroxyl cyclic peptide that is a highly specific MC4-R antagonist or inverse agonist suitable for-use as a specific pharmaceutical in treatment of eating disorders and which is efficacious at low doses.
[0067]Another embodiment of the present invention provides a C-terminus N-alkyl cyclic peptide that is a highly specific MC4-R antagonist or inverse agonist suitable for use as a specific pharmaceutical in treatment of eating disorders and which is efficacious at low doses.

Problems solved by technology

Targeted disruption of the melanocortin-4 receptor results in obesity in mice.
In the elderly as well as in cancer and AIDS patients, wasting diseases can result in undesired loss of body weight, including both the fat and the fat-free compartments.
Wasting diseases can be the result of inadequate intake of food and / or metabolic changes related to illness and / or the aging process.

Method used

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  • Cyclic peptides for treatment for cachexia
  • Cyclic peptides for treatment for cachexia
  • Cyclic peptides for treatment for cachexia

Examples

Experimental program
Comparison scheme
Effect test

example 1

Competitive Inhibition Assay Using [I125]-NDP-α-MSH

[0162]A competitive inhibition binding assay is conducted using membranes prepared using HEK-293 cells transfected with hMC3-R, hMC4-R or hMC5-R gene constructs, and B-16 mouse melanoma cells (containing MC1-R), using respectively 0.4 nM, 0.2 nM, 0.4 nM or 0.1 nM [I125]-NDP-α-MSH (New England Nuclear) in 50 mM HEPES buffer containing 1 mM MgCl2, 2 mM CaCl2, and 5 mM KCl, at pH 7.2. The assay tube also contains a chosen concentration of the test peptide of this invention, typically a 1 μM concentration, for determining its efficacy in inhibiting the binding of [I125]-NDP-α-MSH to its receptor. Non-specific binding is measured by complete inhibition of binding of [I125]-NDP-α-MSH in the assay with the presence of 1 μM NDP-α-MSH.

[0163]The assay mixture is incubated for 90 minutes at room temperature, then filtered and the membranes washed three times with ice cold buffer. The filter is dried and counted in a gamma counter for remaining...

example 2

General Method for EC50 Determination in Functional Activity Assay

[0164]Functional evaluation of peptides at melanocortin receptors is performed by measuring the accumulation of intracellular cAMP in HEK-293 cells expressing hMC3-R, hMC4-R or hMC5-R, and in B-16 mouse melanoma cells expressing MC1-R. Cells suspended in Earle's Balanced Salt Solution containing 10 mM HEPES (pH 7.5), 5 mM MgCl2, 1 mM glutamine, 0.1% albumin and 0.6 mM 3-isobutyl-1-methyl-xanthine, a phosphodiesterase inhibitor, are plated in 96 well plates at a density of 0.5×105 cells per well. Cells are incubated with the test peptides in the presence or absence of α-MSH for 1 hour at 37° C. cAMP levels in the cell lysates are measured using the EIA kit (Amersham). Data analysis and EC50 values are determined using nonlinear regression analysis with Prism Graph-Pad software.

example 3

Functional Status

[0165]The agonist / antagonist status with respect to MC1-R, MC4-R and MC5-R of certain peptides of the invention is determined. Antagonistic activity is determined by measuring the inhibition of α-MSH-induced or NDP-α-MSH-induced cAMP levels following exposure to the peptides as in the preceding descriptions.

[0166]Assay for agonist. Evaluation of the molecules to elicit a functional response in HEK-293 cells expressing hMC4-R for agonistic activity is done by measuring the accumulation of intracellular cAMP following treatment. Confluent HEK-293 cells over-expressing MC4-R are detached by enzyme free cell suspension buffer. Cells are suspended in Earle's Balanced Salt Solution containing 10 mM HEPES (pH 7.5), 1 mM MgCl2, 1 mM glutamine, 0.5% albumin and 0.3 mM 3-isobutyl-1-methyl-xanthine, a phosphodiesterase inhibitor. The cells are plated in a 96 well plates at a density of 0.5×105 cells per well and pre-incubated for 30 minutes. The cells are then challenged with ...

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Abstract

A highly selective melanocortin-4 receptor antagonist cyclic peptide of the formulawhere R1, R2, R3, R4a, R4b, R5, R6, R7, x, y and z are as defined in the specification, and a method of treating body weight disorders, including cachexia, sarcopenia and wasting syndrome or disease, and treating inflammation and immune disorders.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation-in-part application of U.S. patent application Ser. No. 10 / 638,071, filed Aug. 8, 2003, and issued as U.S. Pat. No. 7,176,279 on Feb. 13, 2007, entitled “Cyclic Peptide Compositions and Methods for Treatment of Sexual Dysfunction”, to Shubh D. Sharma, et al., which is a continuation-in-part of International Application No. PCT / US02 / 22196, International Publication No. WO 03 / 006620, filed on Jul. 11, 2002, entitled “Linear and Cyclic Melanocortin Receptor-Specific Peptides”, to Shubh D. Sharma, et al., and the specification and claims thereof of each are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention (Technical Field)[0003]The present invention relates to cyclic peptides that are highly-specific antagonists for the melanocortin-4 receptor (MC4-R), and which may be used in the treatment of a variety of body weight disorders including cachexia, sarcopenia and was...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K38/00A61K38/12C07K7/00
CPCA61K38/12C07K5/0821C07K5/1024C07K7/06C07K7/60Y10S436/811A61P1/14A61P21/00A61P21/06A61P29/00A61P35/00A61P37/00A61P43/00
Inventor SHARMA, SHUBH D.RAJPUROHIT, RAMESHSHADIACK, ANNETTE M.SHI, YI-QUNBURRIS, KEVIN D.
Owner PALATIN TECH INC
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